Oral Care Compositions and Methods of Use

ABSTRACT

The disclosure relates to oral care compositions comprising guanidine in free or orally acceptable salt form, a cationic quaternary ammonium compound (e.g., a pyridinium compound) (e.g., cetyl pyridinium chloride (CPC)), a fluoride source, and optionally a zinc source (e.g., zinc lactate or zinc citrate and zinc oxide) as well as to methods of using and of making these compositions.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.63/247,638, filed Sep. 23, 2021.

FIELD

The disclosure relates to oral care compositions comprising guanidine infree or orally acceptable salt form, a cationic quaternary ammoniumcompound (e.g., a pyridinium compound) (e.g., cetyl pyridinium chloride(CPC)), a fluoride source, and optionally a zinc source (e.g., zinclactate or zinc citrate and zinc oxide) as well as to methods of usingand of making these compositions.

BACKGROUND

Zinc is a well-known antimicrobial agent used in toothpastecompositions. At effective concentrations, zinc has been shown toinhibit bacterial glycolysis and the activity of bacterial proteases.Zinc is also a well-known essential mineral for human health, and hasbeen reported to help strengthen dental enamel and to promote cellrepair. Unfortunately, conventional toothpaste formulations oftenrequire a high concentration of zinc, e.g., 2% by weight or more, toachieve efficacy. At this concentration, the zinc imparts a notablyastringent taste to the composition.

Antibacterial agents are commonly incorporated into oral carecompositions to destroy or inhibit the growth of bacteria that may causedental plaque, caries or dental decay, or bad breath. Many antibacterialagents are cationic in order to interact with the negatively-chargedmicrobial cell membranes. Cetylpyridinium chloride (CPC) is a cationicquaternary ammonium compound used in oral care compositions. CPC isknown to be effective in preventing dental plaque and reducinggingivitis. Generally, improvements in the delivery and efficacy ofantibacterial agents would increase the efficacy and efficiency of oralcare products.

There is thus a need for improved antibacterial oral care formulationsthat do not suffer from the drawbacks of conventional compositions.

BRIEF SUMMARY

Without being bound by theory the addition of guanidine in free or saltform could provide a way to efficiently deliver one or moreantimicrobial agents, such as Cetylpyridinium chloride (CPC), tobiofilms in the oral cavity.

Accordingly, the current formulations offer the advantage of robustmicrobial protection without significantly interfering with thestability of the oral care composition and by allowing for formulationswhich use less zinc and/or improve the delivery of zinc ions to biofilmin the oral cavity. Without being bound by any theory, it is believedthat the presence of the guanidine may help to increase the delivery ofCPC to enamel biofilm which can then an increased effect on inhibitingbacterial growth in the oral cavity of a user. Without being bound bytheory, it is believed that guanidine can function as a chaotrophicagent that is capable of interfering in the electrostatic interactionamong large molecules, e.g., proteins. Accordingly, without being boundby theory, guanidine possibly functions as a delivery agent forantimicrobial or antibacterial agents (e.g., cetylpyridinium chlorideand/or zinc) by altering the physical properties of the biofilm EPSmatrix resulting the destabilization and increased permeability of thematrix. In turn, again without being bound by theory, the resultingdestabilization and increased permeability of the matrix is believed toallow for the uptake of large molecules, e.g., antibacterial agents.

Accordingly, it is believed that the incorporation of guanidine willresult in an improvement in the delivery and efficacy of variousantibacterial agents, e.g., CPC. Therefore, the addition of guanidine tooral care products is believed to improve various antibacterialperformance and provide better biofilm and plaque control.

In one aspect the invention is an oral care composition (Composition1.0) comprising:

-   -   a. guanidine, in free or salt form;    -   b. a cationic quaternary ammonium compound (e.g., a pyridinium        compound) (e.g., cetyl pyridinium chloride (CPC));    -   c. a fluoride source (e.g., sodium fluoride)        For example, the invention contemplates any of the following        compositions (unless otherwise indicated, values are given as        percentage of the overall weight of the composition):    -   1.1 Composition 1.0 wherein the guanidine is in free form.    -   1.2 Composition 1.0, wherein the guanidine is in partial or        whole salt form.    -   1.3 Any of the preceding compositions wherein the guanidine        (e.g., Guanidine HCL) is present in an amount corresponding to        0.3% to 15%, (e.g., 0.4 wt. % to 3 wt. % of the total        composition weight), (e.g., 0.3 wt. %-3 wt. % of the total        composition weight) (e.g., about 0.44% by wt.), (e.g., about        0.45%), (e.g., about 0.9%), (e.g., about 1.5%), (e.g., about        1.8% by wt.).    -   1.4 Any of the preceding compositions wherein the guanidine is        present from 0.1 wt. %-5.0 wt. %. (e.g., about 0.44%, 0.45%,        0.9%, or 1.8% by wt.).    -   1.5 Any of the preceding compositions wherein the guanidine is        present in about 0.44 by wt. % of the total composition weight.    -   1.6 Any of the preceding compositions wherein the guanidine is        present in about 0.45 by wt. % of the total composition weight.    -   1.7 Any of the preceding compositions wherein the guanidine is        present in about 0.9% by wt. % of the total composition weight.    -   1.8 Any of the preceding compositions wherein the guanidine is        present in about 1.5% by wt. % of the total composition weight.    -   1.9 Any of the preceding compositions wherein the guanidine is        present in about 1.8 by wt. % of the total composition weight.    -   1.10 Any of the preceding compositions, wherein the guanidine is        a salt selected from the group consisting of: Guanidine        Hydrochloride (also referred to as guanidinium chloride),        Guanidine Monohydrate, Guanidine Monohydrobromide, Guanidine        Monohydrochloride, Guanidine Monohydroiodine, Guanidine Nitrate,        Guanidine Phosphate, Guanidine Sulfate, and combinations        thereof.    -   1.11 The preceding composition, wherein the guanidine salt is        guanidine hydrochloride.    -   1.12 Any of the preceding compositions, wherein the guanidine is        in the oral care compositions in the form of guanidinium (e.g.,        the conjugate acid).    -   1.13 Any of the preceding compositions wherein the guanidine        ionized by neutralization with an acid or a salt of an acid.    -   1.14 Any of the preceding, wherein the weight of the guanidine        refers to the weight of the salt (e.g., Guanidine HCL) relative        to the total composition weight.    -   1.15 Any of preceding compositions wherein the composition is        ethanol-free.    -   1.16 Any of the preceding compositions further comprising a        fluoride source selected from: stannous fluoride, sodium        fluoride, potassium fluoride, sodium monofluorophosphate, sodium        fluorosilicate, ammonium fluorosilicate, amine fluoride (e.g.,        N′-octadecyltrimethylendiamine-N,N,N′-tris(2-ethanol)-dihydrofluoride),        ammonium fluoride, titanium fluoride, hexafluorosulfate, and        combinations thereof.    -   1.17 Any of the preceding compositions, wherein the cationic        quaternary ammonium compound comprises a pyridinium compound.    -   1.18 The preceding composition, wherein the pyridinium compound        comprises cetylpyridinium chloride (CPC) (e.g., CPC in an amount        from 0.05%-0.125% by wt. relative to the total composition).    -   1.19 The preceding composition, wherein the pyridinium compound        comprises cetyl pyridinium chloride in an amount from        0.05%-0.125% by wt. relative to the total composition (e.g.,        about 0.075% by wt. relative to the total composition).    -   1.20 Any of the preceding compositions wherein the fluoride        source is a fluorophosphate.    -   1.21 Any of the preceding compositions wherein the fluoride        source is sodium monofluorophosphate.    -   1.22 Any of the preceding compositions wherein the fluoride        source is sodium fluoride.    -   1.23 Any of the preceding compositions wherein the fluoride        source is stannous fluoride.    -   1.24 Any of the preceding compositions wherein the fluoride        source is a fluoride salt present in an amount of 0.1 wt. % to 2        wt. % (0.1 wt. %-0.6 wt. %) of the total composition weight        (e.g., sodium fluoride (e.g., about 0.3 wt. %) or sodium        monofluorophosphate).    -   1.25 Any of the preceding compositions wherein the fluoride        source is a soluble fluoride salt which provides fluoride ion in        an amount of from 50 to 25,000 ppm (e.g., 750-2000 ppm, e.g.,        1000-1500 ppm, e.g., about 1000 ppm, e.g., about 1450 ppm)    -   1.26 Any of the preceding compositions wherein the fluoride        source is sodium fluoride which provides fluoride in an amount        from 750-2000 ppm (e.g., about 1450 ppm)    -   1.27 Any of the preceding compositions wherein the fluoride        source is selected from sodium fluoride and sodium        monofluorophosphate and which provides fluoride in an amount        from 1000 ppm-1500 ppm.    -   1.28 Any of the preceding compositions wherein the fluoride        source is sodium fluoride or sodium monofluorophosphate and        which provides fluoride in an amount of about 1450 ppm.    -   1.29 Any of the preceding compositions wherein the pH is between        7.5 and 10.5, e.g., 9.0 to 10.0, e.g., 9.4.    -   1.30 Any of the preceding compositions further comprising        calcium carbonate.    -   1.31 The composition of 1.30, wherein the calcium carbonate is a        precipitated calcium carbonate high absorption (e.g., 20% to 30%        by weight of the composition) (e.g., 25% precipitated calcium        carbonate high absorption).    -   1.32 The composition of 1.31, further comprising a precipitated        calcium carbonate—light (e.g., about 10% precipitated calcium        carbonate—light) (e.g., about 10% natural calcium carbonate).    -   1.33 Any of the preceding compositions further comprising an        effective amount of one or more alkali phosphate salts, e.g.,        sodium, potassium or calcium salts, e.g., selected from alkali        dibasic phosphate and alkali pyrophosphate salts, e.g., alkali        phosphate salts selected from sodium phosphate dibasic,        potassium phosphate dibasic, dicalcium phosphate dihydrate,        calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium        pyrophosphate, sodium tripolyphosphate, disodium        hydrogenorthophosphate, monosodium phosphate, pentapotassium        triphosphate and mixtures of any of two or more of these, e.g.,        in an amount of 1-20%, e.g., 2-8%, e.g., ca. 5%>, by weight of        the composition.    -   1.34 The composition of 1.33, wherein the stannous salt is        selected from stannous fluoride, stannous pyrophosphate, and        combinations thereof.    -   1.35 Any of the preceding compositions comprising tetrapotassium        pyrophosphate, disodium hydrogenorthophosphate, monosodium        phosphate, and pentapotassium triphosphate.    -   1.36 Any of the preceding compositions comprising a        polyphosphate.    -   1.37 The composition of 1.36, wherein the polyphosphate is        tetrasodium pyrophosphate.    -   1.38 The composition of 1.37, wherein the tetrasodium        pyrophosphate is from 0.1-1.0 wt. % (e.g., about 0.5 wt. %).    -   1.39 Any of the preceding compositions further comprising an        abrasive or particulate (e.g., silica).    -   1.40 Any of the preceding compositions wherein the silica is        synthetic amorphous silica. (e.g., 1%-25% by wt.) (e.g., 8%-25%        by wt.)    -   1.41 Any of the preceding composition wherein the silica        abrasives are silica gels or precipitated amorphous silicas,        e.g., silicas having an average particle size ranging from 2.5        microns to 12 microns.    -   1.42 Any of the preceding compositions further comprising a        small particle silica having a median particle size (d50) of 1-5        microns (e.g., 3-4 microns) (e.g., about 5 wt. % Sorbosil AC43        from Ineos Silicas, Warrington, United Kingdom).    -   1.43 Any of the preceding compositions wherein 20-30 wt. % of        the total silica in the composition is small particle silica        (e.g., having a median particle size (d50) of 3-4 microns) and        wherein the small particle silica is about 5 wt. % of the oral        care composition.    -   1.44 Any of the preceding compositions comprising silica wherein        the silica is used as a thickening agent, e.g., particle silica.    -   1.45 Any of the preceding compositions further comprising a        nonionic surfactant, wherein the nonionic surfactant is in an        amount of from 0.5-5%, e.g., 1-2%, selected from poloxamers        (e.g., poloxamer 407), polysorbates (e.g., polysorbate 20),        polyoxyl hydrogenated castor oil (e.g., polyoxyl 40 hydrogenated        castor oil), and mixtures thereof.    -   1.46 Any of the preceding compositions, wherein the poloxamer        nonionic surfactant has a polyoxypropylene molecular mass of        from 3000 to 5000 g/mol and a polyoxyethylene content of from 60        to 80 mol %, e.g., the poloxamer nonionic surfactant comprises        poloxamer 407.    -   1.47 Any of the preceding compositions further comprising        sorbitol, wherein the sorbitol is in a total amount of 10-40%        (e.g., about 23%).    -   1.48 Any of the preceding compositions further comprising        glycerin, wherein the glycerin is in a total amount of 5-20%        (e.g., about 7.5%).    -   1.49 Any of the preceding compositions further comprising        propylene glycol, wherein the propylene glycol is in a total        amount of 5-20% (e.g., about 7%).    -   1.50 Any of the preceding compositions further comprising a zinc        ion source.    -   1.51 The preceding composition, wherein the zinc ion source is        selected from zinc citrate, zinc oxide, zinc sulfate, zinc        silicate, zinc lactate, zinc phosphate, and combinations        thereof.    -   1.52 The preceding composition, wherein the zinc ion source        comprises zinc lactate (e.g., from 0.1%-2% by wt.) (e.g., about        0.28%).    -   1.53 The composition of 1.51, wherein the zinc ion source        comprises zinc citrate and zinc oxide.    -   1.54 The preceding compositions, wherein the ratio of the amount        of zinc oxide (e.g., wt. %) to zinc citrate (e.g., wt. %) is        from 1.5:1 to 4.5:1 (e.g., 2:1, 2.5:1, 3:1, 3.5:1, or 4:1).    -   1.55 Any of the preceding compositions, wherein the zinc citrate        is in an amount of from 0.25 to 0.75 wt. % (e.g., 0.5 wt. %) and        zinc oxide may be present in an amount of from 0.75 to 1.25 wt.        % (e.g., 1.0 wt. %) based on the weight of the oral care        composition.    -   1.56 Any of the preceding compositions wherein the zinc citrate        is about 0.5 wt. %.    -   1.57 Any of the preceding compositions wherein the zinc oxide is        about 1.0 wt. %.    -   1.58 Any of the preceding compositions where the zinc citrate is        about 0.5 wt. % and the zinc oxide is about 1.0 wt. %.    -   1.59 Any of the preceding compositions further comprising a        preservative selected from: benzyl alcohol, Methylisothizolinone        (“MIT”), Sodium bicarbonate, sodium methyl cocoyl taurate        (tauranol), lauryl alcohol, and polyphosphate.    -   1.60 The composition of 1.59, wherein the benzyl alcohol is        present from 0.1-0.6 wt. %, (e.g., 0.1-0.4 wt. %) e.g., about        0.1 wt. %, about 0.2 wt. %, or about 0.3 wt. %.    -   1.61 The composition of 1.60, wherein the benzyl alcohol is        about 0.1 wt. %.    -   1.62 Any of the preceding compositions comprising polymer films.    -   1.63 Any of the preceding compositions comprising flavoring,        fragrance and/or coloring.    -   1.64 The composition of 1.63, wherein the flavoring agent is        sodium saccharin, sucralose, or a mixture thereof.    -   1.65 Any of the preceding compositions, wherein the composition        comprises a thickening agents selected from the group consisting        of carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose        and water soluble salts of cellulose ethers (e.g., sodium        carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl        cellulose).    -   1.66 Any of the preceding compositions, wherein the compositions        comprises sodium carboxymethyl cellulose (e.g., from 0.5 wt.        %-1.5 wt. %)    -   1.67 Any of the preceding compositions comprising from 5%-85%,        e.g., 10%-85%, e.g., 20%-85%, e.g., 30%-85%, e.g., 40%-85%,        e.g., 50%-85%, e.g., 60%-85%, e.g., 70%-85%, e.g., 75%-85%,        e.g., about 10%, e.g., about 20%, e.g., about 30%, e.g., about        40%, e.g., about 50%, e.g., about 60%, e.g., about 70%, e.g.,        about 80%.    -   1.68 Any of the preceding compositions comprising an additional        antibacterial agent selected from halogenated diphenyl ether        (e.g. triclosan), herbal extracts and essential oils (e.g.,        rosemary extract, tea extract, magnolia extract, thymol,        menthol, eucalyptol, geraniol, carvacrol, citral, hinokitol,        catechol, methyl salicylate, epigallocatechin gallate,        epigallocatechin, gallic acid, miswak extract, sea-buckthorn        extract), bisguanide antiseptics (e.g., chlorhexidine, alexidine        or octenidine), benzalkonium chloride, tetradecylpyridinium        chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride        (TDEPC)), phenolic antiseptics, hexetidine, octenidine,        sanguinarine, povidone iodine, delmopinol, salifluor, metal ions        (e.g., zinc salts, for example, zinc chloride, zinc lactate,        zinc sulfate, stannous salts, copper salts, iron salts),        sanguinarine, propolis and oxygenating agents (e.g., hydrogen        peroxide, buffered sodium peroxyborate or peroxycarbonate),        phthalic acid and its salts, monoperthalic acid and its salts        and esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate,        dioctyl sulfosuccinate, salicylanilide, domiphen bromide,        delmopinol, octapinol and other piperidino derivatives, nicin        preparations, chlorite salts; and mixtures of any of the        foregoing.    -   1.69 Any of the preceding compositions comprising an        antioxidant, e.g., selected from the group consisting of        Co-enzyme Q10, PQQ, Vitamin C, Vitamin E, Vitamin A, BHT,        anethole-dithiothione, and mixtures thereof.    -   1.70 Any of the preceding compositions comprising a whitening        agent.    -   1.71 Any of the preceding compositions comprising a whitening        agent selected from a whitening active selected from the group        consisting of peroxides, metal chlorites, perborates,        percarbonates, peroxyacids, hypochlorites, and combinations        thereof.    -   1.72 Any of the preceding compositions further comprising        hydrogen peroxide or a hydrogen peroxide source, e.g., urea        peroxide or a peroxide salt or complex (e.g., such as        peroxyphosphate, peroxycarbonate, perborate, peroxysilicate, or        persulphate salts; for example calcium peroxyphosphate, sodium        perborate, sodium carbonate peroxide, sodium peroxyphosphate,        and potassium persulfate), or hydrogen peroxide polymer        complexes such as hydrogen peroxide-polyvinyl pyrrolidone        polymer complexes.    -   1.73 Any of the preceding compositions further comprising an        agent that interferes with or prevents bacterial attachment,        e.g., ELA or chitosan.    -   1.74 Any of the preceding compositions further comprising a        basic amino acid.    -   1.75 The composition of 1.74, wherein the basic amino acid is        selected from: arginine, lysine, serine, citrullene, ornithine,        creatine, histidine, diaminobutanoic acid, diaminoproprionic        acid, salts thereof or combinations thereof, e.g., wherein the        basic amino acid is arginine in free or salt form. 1.76 Any of        the preceding composition, wherein the oral care composition is        a dentifrice comprising a zwitterionic surfactant, for example a        betaine surfactant, for example cocamidopropylbetaine, e.g., in        an amount of from about 0.1% to about 4.5% by weight, e.g.,        0.5-2% cocamidopropylbetaine by weight of the composition    -   1.77 Any of the preceding compositions comprising:        -   a. about 0.2%-2.5% guanidine (e.g., guanidine HCl) by wt. of            the total composition (e.g., about 0.44%)        -   b. cetylpyridinium chloride (CPC) from 0.05%-0.125% by wt.            relative to the total composition (e.g., CPC in an amount of            about 0.075% by wt. relative to the total composition)        -   c. from 0.1%-0.5% sodium fluoride.    -   1.78 Any of the preceding compositions comprising:        -   a. about 0.2%-2.5% guanidine (e.g., guanidine HCl) by wt. of            the total composition (e.g., about 0.44%)        -   b. cetylpyridinium chloride (CPC) from 0.05%-0.125% by wt.            relative to the total composition (e.g., CPC in an amount of            about 0.075% by wt. relative to the total composition)        -   c. from 0.1%-0.5% sodium fluoride.        -   d. from 0.75%-1.25% zinc oxide (e.g., about 1.0% zinc oxide)        -   e. from 0.25%-0.75% zinc citrate (e.g., about 0.5% zinc            citrate).    -   1.79 Any of the preceding compositions comprising:        -   a. about 0.2%-2.5% guanidine (e.g., guanidine HCl) by wt. of            the total composition (e.g., about 0.44%)        -   b. cetylpyridinium chloride (CPC) from 0.05%-0.125% by wt.            relative to the total composition (e.g., CPC in an amount of            about 0.075% by wt. relative to the total composition)        -   c. from 0.1%-0.5% sodium fluoride.        -   d. from 0.75%-1.25% zinc oxide (e.g., about 1.0% zinc oxide)        -   e. from 0.25%-0.75% zinc citrate (e.g., about 0.5% zinc            citrate)        -   f. from 0.5%-5% arginine (e.g., 1.5% L-arginine).    -   1.80 Any of foregoing compositions comprising:        -   a. about 0.2%-2.5% guanidine (e.g., guanidine HCl) by wt. of            the total composition (e.g., about 0.44%)        -   b. cetylpyridinium chloride (CPC) from 0.05%-0.125% by wt.            relative to the total composition (e.g., CPC in an amount of            about 0.075% by wt. relative to the total composition)        -   c. from 0.1%-0.5% sodium fluoride by wt. of the total            composition        -   d. from 0.1%-1.0% of zinc lactate by wt. of the total            composition (e.g., about 0.22%).    -   1.81 Any of the foregoing compositions comprising:        -   a. about 0.2%-2.5% guanidine (e.g., guanidine HCl) by wt. of            the total composition (e.g., about 0.44%)        -   b. cetylpyridinium chloride (CPC) from 0.05%-0.125% by wt.            relative to the total composition (e.g., CPC in an amount of            about 0.075% by wt. relative to the total composition)        -   c. from 0.1%-0.5% sodium fluoride by wt. of the total            composition        -   d. from 0.1%-1.0% of zinc lactate by wt. of the total            composition (e.g., about 0.22%)        -   e. from 0.5%-5% arginine (e.g., 1.5% L-arginine).    -   1.82 Any of the preceding compositions wherein the composition        is in the form of a toothpaste or a mouthwash, and the guanidine        is guanidine hydrochloride in an amount of 0.4-0.5% by weight.    -   1.83 Any of the preceding compositions wherein the composition        is in the form of a toothpaste comprising        -   0.5-1.5 wt. % zinc lactate,        -   0.05-to 0.1 wt. % CPC,        -   0.4-0.5 wt. % guanidine HCl, and        -   1400-1500 ppm sodium fluoride.    -   1.84 Any of the preceding compositions wherein the composition        is in the form of a toothpaste comprising        -   0.5-1.5 wt. % zinc lactate,        -   0.05-to 0.1 wt. % CPC,        -   0.4-0.5 wt. % guanidine HCl, and        -   1400-1500 ppm sodium fluoride.    -   1.85 Any of the preceding compositions wherein the composition        is in the form of a mouthwash comprising 0.05-to 0.1 wt. % CPC,        0.2-0.3 wt. % zinc lactate, and 0.4-0.5 wt. % guanidine HCl.    -   1.86 Any of the preceding compositions effective upon        application to the oral cavity, e.g., by rinsing, optionally in        conjunction with brushing, to (i) reduce or inhibit formation of        dental caries, (ii) reduce, repair or inhibit pre-carious        lesions of the enamel, e.g., as detected by quantitative        light-induced fluorescence (QLF) or electrical caries        measurement (ECM), (iii) reduce or inhibit demineralization and        promote remineralization of the teeth, (iv) reduce        hypersensitivity of the teeth, (v) reduce or inhibit        gingivitis, (vi) promote healing of sores or cuts in the        mouth, (vii) reduce levels of acid producing bacteria, (viii)        inhibit microbial biofilm formation in the oral cavity, (ix)        raise and/or maintain plaque pH at levels of at least pH 5.5        following sugar challenge, (x) reduce plaque accumulation, (xi)        treat, relieve or reduce dry mouth, (xii) clean the teeth and        oral cavity (xiii) reduce erosion, (xiv) prevents stains and/or        whiten teeth, (xv) immunize the teeth against cariogenic        bacteria; and/or (xvi) promote systemic health, including        cardiovascular health, e.g., by reducing potential for systemic        infection via the oral tissues.    -   1.87 Any of the preceding oral compositions, wherein the oral        composition may be any of the following oral compositions        selected from the group consisting of: a toothpaste or a        dentifrice, a mouthwash or a mouth rinse, a topical oral gel,        and a denture cleanser.    -   1.88 A composition obtained or obtainable by combining the        ingredients as set forth in any of the preceding compositions.    -   1.89 A composition of any of the preceding compositions further        comprising an amino acid (e.g., arginine)    -   1.90 A composition of any of the preceding compositions, wherein        the guanidine is in free or orally acceptable salt form and is        not present as a moiety in one or more larger organic molecules.    -   1.91 The preceding composition, wherein guanidine is present in        free or orally acceptable salt form and the composition does not        comprise an amino acid (e.g., arginine).    -   1.92 The preceding composition, wherein the composition does not        comprise arginine.    -   1.93 A composition obtained or obtainable by combining the        ingredients as set forth in any of the preceding compositions.    -   1.94 A composition for use as set for in any of the preceding        compositions.    -   1.95 Any foregoing composition wherein, upon application of the        composition to the teeth, the guanidine in free or salt form        enhances the antibacterial efficacy of the cationic quaternary        ammonium compound (e.g., CPC) by enhancing its delivery to        bacterial biofilms.

In another embodiment, the invention encompasses a method to improveoral health comprising applying an effective amount of the oralcomposition of any of Composition 1.0 et seq set forth above to the oralcavity of a subject in need thereof, e.g., a method to

-   -   i. reduce or inhibit formation of dental caries,    -   ii. reduce, repair or inhibit early enamel lesions, e.g., as        detected by quantitative light-induced fluorescence (QLF) or        electrical caries measurement (ECM),    -   iii. reduce or inhibit demineralization and promote        remineralization of the teeth,    -   iv. reduce hypersensitivity of the teeth,    -   v. reduce or inhibit gingivitis,    -   vi. promote healing of sores or cuts in the mouth,    -   vii. reduce levels of acid producing bacteria,    -   viii. inhibit microbial bio film formation in the oral cavity,    -   ix. raise and/or maintain plaque pH at levels of at least pH 5.5        following sugar challenge,    -   x. reduce plaque accumulation,    -   xi. treat dry mouth,    -   xii. enhance systemic health, including cardiovascular health,        e.g., by reducing potential for systemic infection via the oral        tissues,    -   xiii. Whiten teeth,    -   xiv. reduce erosion of the teeth,    -   xv. immunize (or protect) the teeth against cariogenic bacteria        and their effects, and/or    -   xvi. clean the teeth and oral cavity.        The invention further comprises the use of sodium bicarbonate,        sodium methyl cocoyl taurate (tauranol), MIT, and benzyl alcohol        and combinations thereof in the manufacture of a Composition of        the Invention, e.g., for use in any of the indications set forth        in the above method of Composition 1.0, et seq.

DETAILED DESCRIPTION

As used herein, the term “dentifrice” means paste, gel, or liquidformulations unless otherwise specified. The dentifrice composition canbe in any desired form such as deep striped, surface striped,multi-layered, having the gel surrounding the paste, or any combinationthereof. Alternatively, the oral composition may be dual phase dispensedfrom a separated compartment dispenser.

As used herein, the term “guanidine” refers to the compound with theformula HNC(NH₂)₂ in free or salt form. The conjugate acid of guanidineis the guanidinium cation, (C(NH₂)⁺ ₃). Derivatives of guanidine mayexist as salts which contain the conjugate acid. Guanidine is a verystrong base in water. In neutral water, one of skill in the art willunderstand that guanidine will most likely exist as guanidinium. One ofskill in the art will understand the circumstances when guanidine existsin the formulation in the protonated guanidinium form. “Guanidine”, asused herein, can refer to, for example, to guanidine or guanidinium, ora salt thereof. Physiologically acceptable salts include those derivedfrom pharmaceutically acceptable inorganic or organic acids or bases,for example acid addition salts formed by acids which form aphysiological acceptable anion, e.g., hydrochloride or bromide salt, andbase addition salts formed by bases which form a physiologicallyacceptable cation, for example those derived from alkali metals such aspotassium and sodium or alkaline earth metals such as calcium andmagnesium. Physiologically acceptable salts may be obtained usingstandard procedures known in the art.

As used herein, an “oral care composition” refers to a composition forwhich the intended use includes oral care, oral hygiene, and/or oralappearance, or for which the intended method of use comprisesadministration to the oral cavity, and refers to compositions that arepalatable and safe for topical administration to the oral cavity, andfor providing a benefit to the teeth and/or oral cavity. The term “oralcare composition” thus specifically excludes compositions which arehighly toxic, unpalatable, or otherwise unsuitable for administration tothe oral cavity. In some embodiments, an oral care composition is notintentionally swallowed, but is rather retained in the oral cavity for atime sufficient to affect the intended utility. The oral carecompositions as disclosed herein may be used in nonhuman mammals such ascompanion animals (e.g., dogs and cats), as well as by humans. In someembodiments, the oral care compositions as disclosed herein are used byhumans. Oral care compositions include, for example, dentifrice andmouthwash. In some embodiments, the disclosure provides mouthwashformulations.

As used herein, “orally acceptable” refers to a material that is safeand palatable at the relevant concentrations for use in an oral careformulation, such as a mouthwash or dentifrice. As used herein, “orallyacceptable carrier” refers to any vehicle useful in formulating the oralcare compositions disclosed herein. The orally acceptable carrier is notharmful to a mammal in amounts disclosed herein when retained in themouth, without swallowing, for a period sufficient to permit effectivecontact with a dental surface as required herein. In general, the orallyacceptable carrier is not harmful even if unintentionally swallowed.Suitable orally acceptable carriers include, for example, one or more ofthe following: water, a thickener, a buffer, a humectant, a surfactant,an abrasive, a sweetener, a flavorant, a pigment, a dye, an anti-cariesagent, an anti-bacterial, a whitening agent, a desensitizing agent, avitamin, a preservative, an enzyme, and mixtures thereof.

Amino Acid

In some aspects, any of Compositions 1.0 et seq can include a basic orneutral amino acid. The basic amino acids which can be used in thecompositions and methods of the invention include not only naturallyoccurring basic amino acids, such as arginine, lysine, and histidine,but also any basic amino acids having a carboxyl group and an aminogroup in the molecule, which are water-soluble and provide an aqueoussolution with a pH of 7 or greater.

For example, basic amino acids include, but are not limited to,arginine, lysine, serine, citrullene, ornithine, creatine, histidine,diaminobutanoic acid, diaminoproprionic acid, salts thereof orcombinations thereof. In a particular embodiment, the basic amino acidsare selected from arginine, citrullene, and ornithine.

In certain embodiments, the basic amino acid is arginine, for example,L-arginine, or a salt thereof.

In another aspect, the compositions of the invention (e.g., any ofCompositions 1.0 et seq) can include a neutral amino acid, which caninclude, but are not limited to, one or more neutral amino acidsselected from the group consisting of alanine, aminobutyrate,asparagine, cysteine, cystine, glutamine, glycine, hydroxyproline,isoleucine, leucine, methionine, phenylalanine, proline, serine,taurine, threonine, tryptophan, tyrosine, valine, and combinationsthereof.

The compositions of the invention are intended for topical use in themouth and so salts for use in the present invention should be safe forsuch use, in the amounts and concentrations provided. Suitable saltsinclude salts known in the art to be pharmaceutically acceptable saltsare generally considered to be physiologically acceptable in the amountsand concentrations provided. Physiologically acceptable salts includethose derived from pharmaceutically acceptable inorganic or organicacids or bases, for example acid addition salts formed by acids whichform a physiological acceptable anion, e.g., hydrochloride or bromidesalt, and base addition salts formed by bases which form aphysiologically acceptable cation, for example those derived from alkalimetals such as potassium and sodium or alkaline earth metals such ascalcium and magnesium. Physiologically acceptable salts may be obtainedusing standard procedures known in the art, for example, by reacting asufficiently basic compound such as an amine with a suitable acidaffording a physiologically acceptable anion.

Fluoride Ion Source

The oral care compositions include one or more fluoride ion sources,e.g., soluble fluoride salts. A wide variety of fluoride ion-yieldingmaterials can be employed as sources of soluble fluoride in the presentcompositions. Examples of suitable fluoride ion-yielding materials arefound in U.S. Pat. No. 3,535,421, to Briner et al.; U.S. Pat. No.4,885,155, to Parran, Jr. et al. and U.S. Pat. No. 3,678,154, to Widderet al., each of which are incorporated herein by reference.Representative fluoride ion sources used with the present invention(e.g., Composition 1.0 et seq.) include, but are not limited to,stannous fluoride, sodium fluoride, potassium fluoride, sodiummonofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate,amine fluoride, ammonium fluoride, and combinations thereof. In certainembodiments the fluoride ion source includes stannous fluoride, sodiumfluoride, sodium monofluorophosphate as well as mixtures thereof. Wherethe formulation comprises calcium salts, the fluoride salts arepreferably salts wherein the fluoride is covalently bound to anotheratom, e.g., as in sodium monofluorophosphate, rather than merelyionically bound, e.g., as in sodium fluoride.

Surfactants

The invention may in some embodiments contain anionic surfactants, e.g.,the Compositions of Composition 1.0, et seq., for example, water-solublesalts of higher fatty acid monoglyceride monosulfates, such as thesodium salt of the monosulfated monoglyceride of hydrogenated coconutoil fatty acids such as sodium N-methyl N-cocoyl taurate, sodiumcocomo-glyceride sulfate; higher alkyl sulfates, such as sodium laurylsulfate; higher alkyl-ether sulfates, e.g., of formulaCH₃(CH₂)_(m)CH₂(OCH₂CH₂)_(n)OS0₃X, wherein m is 6-16, e.g., 10, n is1-6, e.g., 2, 3 or 4, and X is Na or, for example sodium laureth-2sulfate (CH₃(CH₂)₁₀CH₂(OCH₂CH₂)₂OS03Na); higher alkyl aryl sulfonatessuch as sodium dodecyl benzene sulfonate (sodium lauryl benzenesulfonate); higher alkyl sulfoacetates, such as sodium laurylsulfoacetate (dodecyl sodium sulfoacetate), higher fatty acid esters of1,2 dihydroxy propane sulfonate, sulfocolaurate (N-2-ethyl lauratepotassium sulfoacetamide) and sodium lauryl sarcosinate. By “higheralkyl” is meant, e.g., C₆₋₃₀ alkyl. In particular embodiments, theanionic surfactant (where present) is selected from sodium laurylsulfate and sodium ether lauryl sulfate. When present, the anionicsurfactant is present in an amount which is effective, e.g., >0.001% byweight of the formulation, but not at a concentration which would beirritating to the oral tissue, e.g., 1%, and optimal concentrationsdepend on the particular formulation and the particular surfactant. Inone embodiment, the anionic surfactant is present at from 0.03% to 5% byweight, e.g., 1.5%.

In another embodiment, cationic surfactants useful in the presentinvention can be broadly defined as derivatives of aliphatic quaternaryammonium compounds having one long alkyl chain containing 8 to 18 carbonatoms such as lauryl trimethylammonium chloride, cetyl pyridiniumchloride, cetyl trimethylammonium bromide,di-isobutylphenoxyethyldimethylbenzylammonium chloride, coconutalkyltrimethylammonium nitrite, cetyl pyridinium fluoride, and mixturesthereof. Illustrative cationic surfactants are the quaternary ammoniumfluorides described in U.S. Pat. No. 3,535,421, to Briner et al., hereinincorporated by reference. Certain cationic surfactants can also act asgermicides in the compositions.

Illustrative nonionic surfactants of Composition 1.0, et seq., that canbe used in the compositions of the invention can be broadly defined ascompounds produced by the condensation of alkylene oxide groups(hydrophilic in nature) with an organic hydrophobic compound which maybe aliphatic or alkylaromatic in nature. Examples of suitable nonionicsurfactants include, but are not limited to, the Pluronics, polyethyleneoxide condensates of alkyl phenols, products derived from thecondensation of ethylene oxide with the reaction product of propyleneoxide and ethylene diamine, ethylene oxide condensates of aliphaticalcohols, long chain tertiary amine oxides, long chain tertiaryphosphine oxides, long chain dialkyl sulfoxides and mixtures of suchmaterials. In a particular embodiment, the composition of the inventioncomprises a nonionic surfactant selected from polaxamers (e.g.,polaxamer 407), polysorbates (e.g., polysorbate 20), polyoxylhydrogenated castor oils (e.g., polyoxyl 40 hydrogenated castor oil),and mixtures thereof.

In still another embodiment amphoteric surfactants can be used. Suitableamphoteric surfactants, without limitation, are derivatives of C₈₋₂₀aliphatic secondary and tertiary amines having an anionic group such ascarboxylate, sulfate, sulfonate, phosphate or phosphonate. A suitableexample is cocoamidopropyl betaine. One or more surfactants areoptionally present in a total amount of 0.01 weight % to 10 weight %,for example, from 0.05 weight % to 5 weight % or from 0.1 weight % to 2weight % by total weight of the composition.

The surfactant or mixtures of compatible surfactants can be present inthe compositions of the present invention in 0.1% to 5%, in anotherembodiment 0.3% to 3% and in another embodiment 0.5% to 2% by weight ofthe total composition.

Flavoring Agents

The oral care compositions of the invention may also include a flavoringagent. Flavoring agents which are used in the practice of the presentinvention include, but are not limited to, essential oils and variousflavoring aldehydes, esters, alcohols, and similar materials, as well assweeteners such as sodium saccharin. Examples of the essential oilsinclude oils of spearmint, peppermint, wintergreen, sassafras, clove,sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit, andorange. Also useful are such chemicals as menthol, carvone, andanethole. Certain embodiments employ the oils of peppermint andspearmint.

The flavoring agent is incorporated in the oral composition at aconcentration of 0.01 to 1% by weight.

Chelating and Anti-Calculus Agents

The oral care compositions of the invention also may include one or morechelating agents able to complex calcium found in the cell walls of thebacteria. Binding of this calcium weakens the bacterial cell wall andaugments bacterial lysis.

Another group of agents suitable for use as chelating or anti-calculusagents in the present invention are the soluble pyrophosphates. Thepyrophosphate salts used in the present compositions can be any of thealkali metal pyrophosphate salts. In certain embodiments, salts includetetra alkali metal pyrophosphate, dialkali metal diacid pyrophosphate,trialkali metal monoacid pyrophosphate and mixtures thereof, wherein thealkali metals are sodium or potassium. The salts are useful in boththeir hydrated and unhydrated forms. An effective amount ofpyrophosphate salt useful in the present composition is generally enoughto provide at least 0.5 wt. % pyrophosphate ions, 0.9-3 wt. %. Thepyrophosphates also contribute to preservation of the compositions bylowering water activity.

Polymers

The oral care compositions of the invention also optionally include oneor more polymers, such as polyethylene glycols, polyvinyl methyl ethermaleic acid copolymers, polysaccharides (e.g., cellulose derivatives,for example carboxymethyl cellulose, or polysaccharide gums, for examplexanthan gum or carrageenan gum). Acidic polymers, for examplepolyacrylate gels, may be provided in the form of their free acids orpartially or fully neutralized water soluble alkali metal (e.g.,potassium and sodium) or ammonium salts. Certain embodiments include 1:4to 4:1 copolymers of maleic anhydride or acid with another polymerizableethylenically unsaturated monomer, for example, methyl vinyl ether(methoxyethylene) having a molecular weight (M.W.) of about 30,000 toabout 1,000,000. These copolymers are available for example as GantrezAN 139 (M.W. 500,000), AN 1 19 (M.W. 250,000) and S-97 PharmaceuticalGrade (M.W. 70,000), of GAF Chemicals Corporation.

Other operative polymers include those such as the 1:1 copolymers ofmaleic anhydride with ethyl acrylate, hydroxyethyl methacrylate,N-vinyl-2-pyrollidone, or ethylene, the latter being available forexample as Monsanto EMA No. 1 103, M.W. 10,000 and EMA Grade 61, and 1:1copolymers of acrylic acid with methyl or hydroxyethyl methacrylate,methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.

Suitable generally, are polymerized olefinically or ethylenicallyunsaturated carboxylic acids containing an activated carbon-to-carbonolefinic double bond and at least one carboxyl group, that is, an acidcontaining an olefinic double bond which readily functions inpolymerization because of its presence in the monomer molecule either inthe alpha-beta position with respect to a carboxyl group or as part of aterminal methylene grouping. Illustrative of such acids are acrylic,methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxypropionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic,muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic,alpha-phenylacrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic,umbellic, fumaric, maleic acids and anhydrides. Other different olefinicmonomers copolymerizable with such carboxylic monomers includevinylacetate, vinyl chloride, dimethyl maleate and the like. Copolymerscontain sufficient carboxylic salt groups for water-solubility.

A further class of polymeric agents includes a composition containinghomopolymers of substituted acrylamides and/or homopolymers ofunsaturated sulfonic acids and salts thereof, in particular wherepolymers are based on unsaturated sulfonic acids selected fromacrylamidoalykane sulfonic acids such as 2-acrylamide 2 methylpropanesulfonic acid having a molecular weight of about 1,000 to about2,000,000, described in U.S. Pat. No. 4,842,847, Jun. 27, 1989 to Zahid,incorporated herein by reference.

Another useful class of polymeric agents includes polyamino acids,particularly those containing proportions of anionic surface-activeamino acids such as aspartic acid, glutamic acid and phosphoserine, asdisclosed in U.S. Pat. No. 4,866,161 Sikes et al., incorporated hereinby reference.

In preparing oral care compositions, it is sometimes necessary to addsome thickening material to provide a desirable consistency or tostabilize or enhance the performance of the formulation. In certainembodiments, the thickening agents are carboxyvinyl polymers,carrageenan, hydroxyethyl cellulose and water soluble salts of celluloseethers such as sodium carboxymethyl cellulose and sodium carboxymethylhydroxyethyl cellulose. Natural gums such as karaya, gum arabic, and gumtragacanth can also be incorporated. Colloidal magnesium aluminumsilicate or finely divided silica can be used as component of thethickening composition to further improve the composition's texture. Incertain embodiments, thickening agents in an amount of about 0.5% toabout 5.0% by weight of the total composition are used.

Abrasives

Natural calcium carbonate is found in rocks such as chalk, limestone,marble and travertine. It is also the principle component of egg shellsand the shells of mollusks. The natural calcium carbonate abrasive ofthe invention is typically a finely ground limestone which mayoptionally be refined or partially refined to remove impurities. For usein the present invention, the material has an average particle size ofless than 10 microns, e.g., 3-7 microns, e.g., about 5.5 microns. Forexample a small particle silica may have an average particle size (D50)of 2.5-4.5 microns. Because natural calcium carbonate may contain a highproportion of relatively large particles of not carefully controlled,which may unacceptably increase the abrasivity, preferably no more than0.01%, preferably no more than 0.004% by weight of particles would notpass through a 325 mesh. The material has strong crystal structure, andis thus much harder and more abrasive than precipitated calciumcarbonate. The tap density for the natural calcium carbonate is forexample between 1 and 1.5 g/cc, e.g., about 1.2 for example about 1.19g/cc. There are different polymorphs of natural calcium carbonate, e.g.,calcite, aragonite and vaterite, calcite being preferred for purposes ofthis invention. An example of a commercially available product suitablefor use in the present invention includes Vicron® 25-11 FG from GMZ.

Precipitated calcium carbonate is generally made by calcining limestone,to make calcium oxide (lime), which can then be converted back tocalcium carbonate by reaction with carbon dioxide in water. Precipitatedcalcium carbonate has a different crystal structure from natural calciumcarbonate. It is generally more friable and more porous, thus havinglower abrasivity and higher water absorption. For use in the presentinvention, the particles are small, e.g., having an average particlesize of 1-5 microns, and e.g., no more than 0.1%, preferably no morethan 0.05% by weight of particles which would not pass through a 325mesh. The particles may for example have a D50 of 3-6 microns, forexample 3.8=4.9, e.g., about 4.3; a D50 of 1-4 microns, e.g., 2.2-2.6microns, e.g., about 2.4 microns, and a D10 of 1-2 microns, e.g.,1.2-1.4, e.g., about 1.3 microns. The particles have relatively highwater absorption, e.g., at least 25 g/100 g, e.g., 30-70 g/100 g.Examples of commercially available products suitable for use in thepresent invention include, for example, Carbolag® 15 Plus from LagosIndustria Quimica.

In certain embodiments the any of the oral care composition of thedisclosure (e.g., any of Composition 1.0 et seq) may comprise additionalcalcium-containing abrasives, for example calcium phosphate abrasive,e.g., tricalcium phosphate (Ca₃(PO₄)₂), hydroxyapatite(Ca₁₀(PO₄)₆(OH)₂), or dicalcium phosphate dihydrate (CaHPO₄.2H₂O, alsosometimes referred to herein as DiCal) or calcium pyrophosphate, and/orsilica abrasives, sodium metaphosphate, potassium metaphosphate,aluminum silicate, calcined alumina, bentonite or other siliceousmaterials, or combinations thereof. Any silica suitable for oral carecompositions may be used, such as precipitated silicas or silica gels.For example synthetic amorphous silica. Silica may also be available asa thickening agent, e.g., particle silica. For example, the silica canalso be small particle silica (e.g., Sorbosil AC43 from Ineos Silicas,Warrington, United Kingdom). However the additional abrasives arepreferably not present in a type or amount so as to increase the RDA ofthe dentifrice to levels which could damage sensitive teeth, e.g.,greater than 130.

Enzymes

The oral care compositions of the disclosure (e.g., any of Compositions1.0 et seq) may also optionally include one or more enzymes. Usefulenzymes include any of the available proteases, glucanohydrolases,endoglycosidases, amylases, mutanases, lipases and mucinases orcompatible mixtures thereof. In certain embodiments, the enzyme is aprotease, dextranase, endoglycosidase and mutanase. In anotherembodiment, the enzyme is papain, endoglycosidase or a mixture ofdextranase and mutanase. Additional enzymes suitable for use in thepresent invention are disclosed in U.S. Pat. No. 5,000,939 to Dring etal., U.S. Pat. Nos. 4,992,420; 4,355,022; 4,154,815; 4,058,595;3,991,177; and 3,696,191 all incorporated herein by reference. An enzymeof a mixture of several compatible enzymes in the current inventionconstitutes 0.002% to 2.0% in one embodiment or 0.05% to 1.5% in anotherembodiment or in yet another embodiment 0.1% to 0.5%.

Water

Water is present in the oral compositions of the invention. Water,employed in the preparation of commercial oral compositions should bedeionized and free of organic impurities. Water commonly makes up thebalance of the compositions and in certain aspects of any of the oralcare compositions of the disclosure (e.g., any of Composition 1.0 etseq), includes: 5% to 45%, e.g., 10% to 20%, e.g., 25-35%, by weight ofthe oral compositions. This amount of water includes the free waterwhich is added plus that amount which is introduced with other materialssuch as with sorbitol or silica or any components of the invention. TheKarl Fischer method is a one measure of calculating free water.

Humectants

In certain aspects the oral care compositions of the disclosure (e.g.,any of Composition 1.0 et seq), comprise a humectant to reduceevaporation and also contribute towards preservation by lowering wateractivity. Certain humectants can also impart desirable sweetness orflavor to the compositions. The humectant, on a pure humectant basis,generally includes 15% to 70% in one embodiment or 30% to 65% in anotherembodiment by weight of the composition.

Suitable humectants include edible polyhydric alcohols such asglycerine, sorbitol, xylitol, propylene glycol as well as other polyolsand mixtures of these humectants. Mixtures of glycerin and sorbitol maybe used in certain embodiments as the humectant component of thecompositions herein.

The present invention in its method aspect involves applying to the oralcavity a safe and effective amount of the compositions described herein.

The compositions and methods according to the invention are useful to amethod to protect the teeth by facilitating repair and remineralization,in particular to reduce or inhibit formation of dental caries, reduce orinhibit demineralization and promote remineralization of the teeth,reduce hypersensitivity of the teeth, and reduce, repair or inhibitearly enamel lesions, e.g., as detected by quantitative light-inducedfluorescence (QLF) or electronic caries monitor (ECM).

Quantitative Light-induced Fluorescence is a visible light fluorescencethat can detect early lesions and longitudinally monitor the progressionor regression. Normal teeth fluoresce in visible light; demineralizedteeth do not or do so only to a lesser degree. The area ofdemineralization can be quantified and its progress monitored. Bluelaser light is used to make the teeth auto fluoresce. Areas that havelost mineral have lower fluorescence and appear darker in comparison toa sound tooth surface. Software is used to quantify the fluorescencefrom a white spot or the area/volume associated with the lesion.Generally, subjects with existing white spot lesions are recruited aspanelists. The measurements are performed in vivo with real teeth. Thelesion area/volume is measured at the beginning of the clinical. Thereduction (improvement) in lesion area/volume is measured at the end of6 months of product use. The data is often reported as a percentimprovement versus baseline.

Electrical Caries Monitoring is a technique used to measure mineralcontent of the tooth based on electrical resistance. Electricalconductance measurement exploits the fact that the fluid-filled tubulesexposed upon demineralization and erosion of the enamel conductelectricity. As a tooth loses mineral, it becomes less resistive toelectrical current due to increased porosity. An increase in theconductance of the patient's teeth therefore may indicatedemineralization. Generally, studies are conducted of root surfaces withan existing lesion. The measurements are performed in vivo with realteeth. Changes in electrical resistance before and after 6-monthtreatments are made. In addition, a classical caries score for rootsurfaces is made using a tactile probe. The hardness is classified on athree-point scale: hard, leathery, or soft. In this type of study,typically the results are reported as electrical resistance (highernumber is better) for the ECM measurements and an improvement inhardness of the lesion based on the tactile probe score.

Test methods for the desensitizing properties of the compositionsdescribed herein, uses the method described in U.S. Pat. No. 5,589,159,the disclosure of which is incorporated by reference herein in itsentirety. This method measures the hydraulic conductance of materials,providing an objective reduction in fluid flow that correlates withreduction in fluid flow in dentinal tubules. In this method, intacthuman molars free from caries and restorations are sectionedperpendicularly to the long axis of the tooth with a metallurgical sawto form thin sections, or discs, from about 0.4 to about 0.8 mm thick.Sections containing dentin and free of enamel were selected for testingand then etched with citric acid solution to remove the smear layer.Each disc was mounted into a split chambered device described in J.Dent. Research, 57: 187 (1978) which is a special leak-proof chamberconnected to a pressurized fluid reservoir containing a tissue culturefluid. By using a mixture of pressurized nitrogen and carbon dioxidegas, the fluid can be made at physiological pH. To further ensureaccuracy, the discs were wetted with artificial saliva (phosphate buffersaline, PBS) to approximate intra-oral conditions. The apparatusincludes a glass capillary tube attached to a flow sensor (FLODEC,DeMarco Engineering SA, Geneva). An air bubble is injected into theglass capillary tube. By measuring the displacement of the bubble as afunction of time, fluid flow through the dentin disc can be measured.Fluid flow is equivalent to the dentin permeability.

The Compositions of the Invention are thus useful in a method to reduceearly lesions of the enamel (as measured by QLF or ECM) relative to acomposition lacking effective amounts of fluorine and/or arginine.

The Compositions of the invention are additionally useful in methods toreduce harmful bacteria in the oral cavity, for example methods toreduce or inhibit gingivitis, reduce levels of acid producing bacteria,to increase relative levels of arginolytic bacteria, inhibit microbialbiofilm formation in the oral cavity, raise and/or maintain plaque pH atlevels of at least pH 5.5 following sugar challenge, reduce plaqueaccumulation, and/or clean the teeth and oral cavity.

Finally, by increasing the pH in the mouth and discouraging pathogenicbacteria, the Compositions of the Invention are useful to promotehealing of sores or cuts in the mouth.

The compositions and methods according to the invention (e.g.,Composition 1.0 et seq) can be incorporated into oral compositions forthe care of the mouth and teeth such as toothpastes, transparent pastes,gels, mouth rinses, sprays and chewing gum.

Enhancing oral health also provides benefits in systemic health, as theoral tissues can be gateways for systemic infections. Good oral healthis associated with systemic health, including cardiovascular health. Thecompositions and methods of the invention provide particular benefitsbecause basic amino acids, especially arginine, are sources of nitrogenwhich supply NO synthesis pathways and thus enhance microcirculation inthe oral tissues. Providing a less acidic oral environment is alsohelpful in reducing gastric distress and creates an environment lessfavorable to Heliobacter, which is associated with gastric ulcers.Arginine in particular is required for high expression of specificimmune cell receptors, for example T-cell receptors, so that argininecan enhance an effective immune response. The compositions and methodsof the invention are thus useful to enhance systemic health, includingcardiovascular health.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by reference in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls. It is understoodthat when formulations are described, they may be described in terms oftheir ingredients, as is common in the art, notwithstanding that theseingredients may react with one another in the actual formulation as itis made, stored and used, and such products are intended to be coveredby the formulations described.

The following examples further describe and demonstrate illustrativeembodiments within the scope of the present invention. The examples aregiven solely for illustration and are not to be construed as limitationsof this invention as many variations are possible without departing fromthe spirit and scope thereof. Various modifications of the invention inaddition to those shown and described herein should be apparent to thoseskilled in the art and are intended to fall within the appended claims.

EXAMPLES Example 1 CPC Delivery and Biofilm Viability—Test 1

Saliva-derived biofilms are cultured on HAP disk at 37 C under 5% CO2.The biofilms are cultured in McBain media supplemented with hemin andvitamin K for a total of ˜60 hours. The media are replaced twice daily(˜12 hour intervals). The resulting biofilm culture is treated once withmouthwash samples (table below) for 2 minutes under agitation (80 rpm).The biofilms are washed twice at 5 minute intervals under agitation (80rpm). Following treatment, the biofilms are allowed to recover for 3hours in sterile dH2O at 37 C prior to biofilm harvesting by sonicationto dislodge and suspend the bacteria. The collected bacteria areassessed for total biomass via Syto9 staining and viability usingBaclight Bacterial Viability Kit (Promega) to quantify approximate ATP(expressed as relative luminescence units; RLU) content in the biofilms.Bacterial viability is normalized based Syto9 staining of the biofilmsamples.

TABLE 1 Mouthwash samples - CPC Delivery Mouthwash comprising FormulaCPC Delivered (wt. %): Designation (ppm) StErr Untreated Control 1 0 0(negative control) 0.075% CPC Control 2 1.68 0.49 (positive control)0.075% CPC, Formula A 1.82 0.66 0.44% Guanidine

The mouthwashes are evaluated for CPC delivery in biofilm, as well asbacterial ATP which serve as a measure of viability, i.e., lower levelsof ATP indicate that viable biofilm are decreased. Importantly, the datain Table 1 demonstrates an increase in CPC delivery with the addition ofguanidine. The results in Table 2 demonstrate that the addition ofguanidine also decreases the amount of viable biofilm in vitro:

TABLE 2 Mouthwash Biofilm comprising Formula viability % Reduction (wt.%): Designation (ATP:RLU) StErr vs. CPC Untreated Control 1 3,292,313828,678.6 N/A (negative control) 0.075% CPC Control 2 3,182,740482,953.2 0 (positive control) 0.075% CPC, Formula A 2,485,047 482,953.221.9% 0.44% Guanidine

From Table 2 increase in CPC delivery is inversely related to bacterialviability with a reduction in ATP levels as the guanidine concentrationincrease. Without being bound by theory, this data suggests thatguanidine may be capable in enhancing the antibacterial efficacy of CPCby driving an improvement in CPC delivery in the biofilms.

Example 2 CPC Delivery and Biofilm Viability—Test 2

Saliva-derived biofilms are cultured on HAP disk at 37 C under 5% CO2.The biofilms are cultured in McBain media supplemented with hemin andvitamin K for a total of ˜60 hours. The media are replaced twice daily(˜12 hour intervals). The resulting biofilm culture is treated once withmouthwash slurries (table below) for 2 minutes under agitation (80 rpm).The biofilms are washed twice at 5 minute intervals under agitation (80rpm). Following treatment, the biofilms are allowed to recover for 3hours in sterile dH2O at 37 C prior to biofilm harvesting by sonicationto dislodge and suspend the bacteria. The collected bacteria areassessed for total biomass via Syto9 staining and viability usingBaclight Bacterial Viability Kit (Promega) to quantify approximate ATP(expressed as relative luminescence units; RLU) content in the biofilms.Bacterial viability is normalized based Syto9 staining of the biofilmsamples.

TABLE 3 Mouthwash samples - CPC Delivery Mouthwash comprising FormulaCPC Delivered (wt. %): Designation (ppm) StErr Untreated Control 3 0 0(negative control) 0.075% CPC Control 4 1.99 0.38 (positive control)0.075% CPC, Formula B 2.14 0.24 0.28% zinc lactate, 0.44% Guanidine

The mouthwashes are evaluated for CPC delivery in biofilm, as well asbacterial ATP which serve as a measure of viability, i.e., lower levelsof ATP indicate that viable biofilm are decreased. Importantly, the datain Table 3 demonstrates an increase in CPC delivery with the addition ofguanidine and zinc lactate. The results in Table 2 demonstrate that theaddition of guanidine also decreases the amount of viable biofilm invitro:

TABLE 4 Mouthwash Biofilm comprising Formula viability % Reduction (wt.%): Designation (ATP:RLU) StErr vs. CPC Untreated Control 1 3,292,313828,678.6 N/A (negative control) 0.075% CPC Control 2 3,247,687973,586.8 0 (positive control) 0.075% CPC, Formula A 2,467,033 703,98324% 0.28% zinc lactate, 0.44% Guanidine

From Table 4 increase in CPC delivery is inversely related to bacterialviability with a reduction in ATP levels as the guanidine concentrationincrease. Without being bound by theory, this data again suggests thatguanidine may be capable in enhancing the antibacterial efficacy of CPCby driving an improvement in CPC delivery in the biofilms. Moreover,without being bound by theory, the addition of zinc lactate may furtherreduce the amount of viable biofilm in vitro.

Example 3

Mouthwash Formulas used in above Tables 1˜4 are as follows:(*All ingredients listed by wt. % relative to the total composition)

Ingredients Control 2 Formula A Control 4 Formula B Demineralized Waterq. s. q. s. q. s. q. s. Nonionic Surfactant 0.4 0.4 0.4 0.4 Color,Flavoring and 0.1735 0.1735 0.1735 0.1735 Sweeteners Cetylpyridinium0.0750 0.0750 0.0750 0.075 Chloride Preservative 0.1 0.1 0.1 0.1 99.5%Vegetable 7.5 7.5 7.5 7.5 Refined Glycerin Non-Crystal Sorbitol 5.5 5.55.5 5.5 Propylene glycol 7 7 7 7 Alkali Phosphate Salt 0.1 0.1 — — pHAdjuster 0.1 0.01 0.05 0.05 Sodium Fluoride 0.05 0.05 0.05 0.05Guanidine HCl — 0.44 — 0.44 Zinc Lactate — — 0.28 0.28 Dihydrate Total100 100 100 100

Example 4

In one representative formulation, a dentifrice will comprise thefollowing:

-   -   a. About 1.0 wt. % zinc lactate    -   b. 0.075 wt. % CPC    -   c. About 0.45 wt. % guanidine HCL    -   d. About 1450 ppm sodium fluoride; and water.

In one representative formulation, a dentifrice will comprise thefollowing:

-   -   a. 0.075 wt. % CPC    -   b. About 0.45 wt. % guanidine HCL    -   c. About 1450 ppm sodium fluoride; and water.        Wherein the dentifrices are expected to enhance CPC delivery        into biofilms, relative to certain CPC containing formulations        without guanidine, and improve the antibacterial efficacy of        CPC.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by referenced in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls.

Unless otherwise specified, all percentages and amounts expressed hereinand elsewhere in the specification should be understood to refer topercentages by weight of the entire composition. The amounts given arebased on the active weight of the material.

While the present invention has been described with reference toembodiments, it will be understood by those skilled in the art thatvarious modifications and variations may be made therein withoutdeparting from the scope of the present invention as defined by theappended claims.

1. An oral care composition comprising: a. guanidine, in free or orallyacceptable salt form; b. a cationic quaternary ammonium compound; and c.a fluoride source.
 2. The oral care composition of claim 1, wherein theguanidine is in free form.
 3. The oral care composition of claim 1,wherein the guanidine is in partial or whole salt form.
 4. The oral carecomposition of claim 1, wherein the guanidine is present in an amountcorresponding to 0.3% to 15% by wt. of the total composition weight. 5.The oral care composition of claim 1, wherein the guanidine is presentfrom 0.1 wt. %-5.0 by wt. % of the total composition weight.
 6. The oralcare composition of claim 1, wherein the guanidine is present in anamount of about 0.45 by wt. % of the total composition weight.
 7. Theoral care composition of claim 1, wherein the guanidine is selected fromthe group consisting of: Guanidine Hydrochloride, Guanidine Monohydrate,Guanidine Monohydrobromide, Guanidine Monohydrochloride, GuanidineMonohydroiodine, Guanidine Nitrate, Guanidine Phosphate, GuanidineSulfate, and combinations thereof.
 8. The oral care composition of claim1, wherein the guanidine is in the oral care compositions in the form ofa guanidinium salt.
 9. The oral care composition of claim 1, wherein thefluoride source is selected from: stannous fluoride, sodium fluoride,potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate,ammonium fluorosilicate, amine fluoride, ammonium fluoride, titaniumfluoride, hexafluorosulfate, and combinations thereof.
 10. The oral carecomposition of claim 9, wherein the fluoride source is sodium fluoride.11. The oral composition of claim 1, wherein the composition furthercomprises a zinc ion source.
 12. The oral care composition of claim 11,wherein the zinc ion source is selected from zinc citrate, zinc oxide,zinc sulfate, zinc silicate, zinc lactate, zinc phosphate, andcombinations thereof.
 13. The oral care composition of claim 12, whereinthe zinc ion source comprises zinc lactate.
 14. The oral carecomposition of claim 12, wherein the zinc ion source comprises zinccitrate and zinc oxide.
 15. The oral care composition of claim 14,wherein the ratio by weight of the amount of zinc oxide to zinc citrateis from 1.5:1 to 4.5:1.
 16. The oral care composition of claim 15,wherein the zinc citrate is in an amount of from 0.25 to 0.75 wt. % andzinc oxide may be present in an amount of from 0.75 to 1.25 wt. % basedon the weight of the oral care composition.
 17. The oral carecomposition of claim 1, wherein the oral composition may be any of thefollowing oral compositions selected from the group consisting of: atoothpaste or a dentifrice, a mouthwash or a mouth rinse, a topical oralgel, and a denture cleanser.
 18. The oral care composition of claim 1,wherein the composition is in the form of a mouthwash comprising 0.05-to0.1 wt. % CPC, 0.2-0.3 wt. % zinc lactate, and 0.4-0.5 wt. % guanidineHCl.
 19. The oral care composition of claim 1, wherein the compositionis obtained or obtainable by combining the ingredients as set forth inany of the preceding compositions.
 20. A method to improve oral healthcomprising applying an effective amount of the oral composition of claim1 to the oral cavity of a subject in need thereof, wherein the method iseffective to: i. reduce or inhibit formation of dental caries, ii.reduce, repair or inhibit early enamel lesions, iii. reduce or inhibitdemineralization and promote remineralization of the teeth, iv. reducehypersensitivity of the teeth, v. reduce or inhibit gingivitis, vi.promote healing of sores or cuts in the mouth, vii. reduce levels ofacid producing bacteria, viii. to increase relative levels ofarginolytic bacteria, ix. inhibit microbial bio film formation in theoral cavity, x. raise and/or maintain plaque pH at levels of at least pH5.5 following sugar challenge, xi. reduce plaque accumulation, xii.treat dry mouth, xiii. enhance systemic health, including cardiovascularhealth, xiv. whiten teeth, xv. reduce erosion of the teeth, xvi.immunize (or protect) the teeth against cariogenic bacteria and theireffects, and/or xvii. clean the teeth and oral cavity.